Evaluation of WO2013117503 and WO2013117504: the use of PI3K inhibitors to treat cough or idiopathic pulmonary fibrosis

Two applications claim the use of the closely related, broad spectrum phosphatidylinositol 3-kinase inhibitors 2,4-difluoro-N-{2-(methoxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide (GSK-2126458) and 2,4-difluoro-N-{2-(methoxy)-5-[4-(4-morpholino)-6-quinazolinyl]-3-pyridinyl}benzenesulfonamide for the treatment of idiopathic pulmonary fibrosis and cough, respectively. Some in vitro data are presented in support of these claimed utilities. Since the filing of these applications, GSK-2126458 has commenced a dose-finding Phase I study in patients with idiopathic pulmonary fibrosis.     

三个非核苷类逆转录酶抑制剂S-DABO类衍生物的体外抗HIV作用

本文对3个新S-DABO类衍合物 (RZK-4、RZK-5、RZK-6) 的体外抗HIV活性进行了研究。化合物RZK-4、RZK-5和RZK-6在200 µg·mL⁻¹的浓度下均能完全抑制HIV-1逆转录酶的活性。3个化合物对多种细胞均呈现出低毒性, 且均在较低浓度下具有抑制HIV-1病毒实验株、临床株和耐药株的作用, 治疗指数为3 704～38 462。其中, 化合物RZK-6对HIV-1耐药株HIV-1_IIIB A17具有非常显著的抑制作用。结果表明, 这3种S-DABO类衍生物有良好的体外抗HIV-1作用, 具有开发成为抗HIV-1药物的前景。     

Synthesis and Cytotoxic Activity of Novel Amidine Analogues of Bis(2‐chloroethyl)amine

Novel nitrogen mustard agents 7 – 12 involving 4‐(N,N‐bis(2‐chloroethyl)aminophenyl)propylamine linked to a 5‐(4‐N‐alkylamidinophenyl)‐2‐furancarboxylic acid moiety by the formation of an amide bond have been synthesized, characterized, and evaluated for their in‐vitro cytotoxic activity against MDA‐MB‐231 and MCF‐7 human breast cancer cells. Evaluation of the cytotoxicity of 7 – 12 employing a MTT assay and inhibition of [³H]thymidine incorporation into DNA demonstrated that these compounds exhibit remarkable cytotoxic effects in comparison with 4‐[bis(2‐chloroethyl)amino]benzenebutanoic acid. Compounds 7 and 9 , which possess a cationic amidine and 4,5‐dihydro‐1H‐imidazol function moiety are approximately ten times more potent than 4‐[bis(2‐chloroethyl)amino]benzenebutanoic acid. The new compounds were evaluated as DNA topoisomerase II inhibitors. The cytotoxicity of the compounds 7 – 12 correlates with their DNA‐binding affinities and their relative potency as topoisomerase II inhibitors.